BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk

Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by Npr1. However, BNP also binds to its cognate receptor, NPRC encoded by Npr3 with equal potency. Moreover, natriuretic peptides (NP) signal through the Gi-couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here we report that Npr3 expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via Gq-couped PLCb-Ca2+ signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca2+ responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice.

Prolonged Administration of Rudgea viburnoides (Cham.) Benth. Prevents Impairment of Redox Status, Renal Dysfunction, and Cardiovascular Damage in 2K1C-Hypertensive Rats by Inhibiting ACE Activity and NO-GMPC Pathway Activation

Rudgea viburnoides is widely found in the Brazilian Cerrado, and commonly used in Brazilian folk medicine. In this study, we evaluated the effects of prolonged administration of the aqueous extract from R. viburnoides leaves (AERV) on impaired redox status, renal dysfunction, and cardiovascular damage in 2K1C hypertensive rats, as well as its chemical composition by LC-DAD-MS. Renal hypertension (two kidney, one-clip model) was surgically induced in male Wistar rats and AERV (30, 100 and 300 mg/kg) was administered orally five weeks after surgery for 28 days. Renal function was assessed and urinary electrolytes, pH, and density were measured. Electrocardiography, blood pressure and heart rate were recorded. Cardiac and mesenteric vascular beds were isolated for cardiac morphometry and evaluation of vascular reactivity, and aortic rings were also isolated for measurement of cyclic guanosine monophosphate levels, and the redox status was assessed. Prolonged treatment with AERV preserved urine excretion and electrolyte levels (Na+, K+, Ca2+ and Cl−), reversed electrocardiographic changes, left ventricular hypertrophy and changes in vascular reactivity induced by hypertension, and reduced blood pressure and heart rate. This effect was associated with a positive modulation of tissue redox state, activation of the NO/cGMP pathway, and inhibition of the angiotensin-converting enzyme. Glycosylated iridoids, chlorogenic acids, glycosylated triterpenes, O-glycosylated flavonols, and triterpenoid saponins were annotated. AERV showed no acute toxicity in female Wistar rats. Therefore, AERV treatment reduced the progression of cardiorenal disease in 2K1C hypertensive rats, which can be involved with an important attenuation of oxidative stress, angiotensin-converting enzyme inhibition, and activation of the NO/cGMP pathway.

The Role of sGC Stimulators and Activators in Heart Failure With Reduced Ejection Fraction

Over the past decade, soluble guanylate cyclase (sGC) activators and stimulators have been developed and studied to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF). The sGC enzyme plays an important role in the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway, that has been largely untargeted by current guideline directed medical therapy (GDMT) for HFrEF. Disruption of the NO-sCG-cGMP pathway can be widely observed in patients with HFrEF leading to endothelial dysfunction. The disruption is caused by an oxidized state resulting in low bioavailability of NO and cGMP. The increase in reactive oxygen species can also result in an oxidized, and subsequently heme free, sGC enzyme that NO is unable to activate, furthering the endothelial dysfunction. The novel sGC stimulators enhance the sensitivity of sGC to NO, and independently stimulate sGC, while the sGC activators target the oxidized and heme free sGC to stimulate cGMP production. This review will discuss the pathophysiologic basis for sGC stimulator and activator use in HFrEF, review the pre-clinical and clinical data, and propose a place in the HFrEF armamentarium for this novel pharmacotherapeutic class.

2-Arachidonoylglycerol as an Endogenous Cue Negatively Regulates Attachment of the Mussel Perna viridis

Endocannabinoids play important roles in the functioning of various physiological systems in humans and non-mammalian animals, including invertebrates. However, information concerning their roles in physiological functions in members of the phylum Mollusca is scarce. Here the hypothesis that the endocannabinoids are involved in mediating settlement of marine invertebrates was tested. Two endocannabinoids [N-arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG)], and two endocannabinoid-like lipids [N-Oleoylethanolamide (OEA) and N-Palmitoylethanolamide (PEA)] were detected in the green mussel Perna viridis. In particular, 2-AG was present at significantly higher levels in unattached P. viridis compared with attached mussels. The in vivo level of 2-AG was inversely correlated with the attachment activity of P. viridis. Furthermore, exposure to synthetic 2-AG inhibited attachment of P. viridis in a reversible manner. Transcriptomic analysis suggested that up-regulation of 2-AG synthase (Phospholipase C-β, PLC-β) and down-regulation of its degrading enzyme (Monoacylglycerol lipase, MAGL) resulted in higher levels of 2-AG in unattached mussels. A putative mechanism for the negative regulation of mussel attachment by 2-AG is proposed that involves a Ca2+- Nitric oxide (NO)- cyclic guanosine monophosphate (cGMP) pathway. This study broadens our understanding of the evolution and roles of the endocannabinoid system in animals, and reveals an endogenous regulatory cue for mussel attachment.

45 years of cGMP research in Dictyostelium: Understanding the regulation and function of the cGMP pathway for cell movement and chemotaxis

In Dictyostelium chemoattractants induce a fast cGMP response that mediates myosin filament formation in the rear of the cell. The major cGMP signaling pathway consists of a soluble guanylyl cyclase sGC, a cGMP-stimulated cGMP-specific phosphodiesterase and the cGMP-target protein GbpC. Here we combine published experiments with many unpublished experiments performed in the past 45 years on the regulation and function of the cGMP signaling pathway. The chemoattractants stimulate heterotrimeric Gαβγ and monomeric Ras proteins. A fraction of the soluble guanylyl cyclase sGC binds with high affinity to a limited number of membrane binding site, which is essential for sGC to become activated by Ras and Gα proteins. sGC can also bind to F-actin; binding to branched F-actin in pseudopods enhances basal sGC activity, whereas binding to parallel F-actin in the cortex reduces sGC activity. The cGMP pathway mediates cell polarity by inhibiting the rear: in unstimulated cells by sGC activity in the branched F-actin of pseudopods, in a shallow gradient by stimulated cGMP formation in pseudopods at the leading edge, and during cAMP oscillation to erase the previous polarity and establish a new polarity axis that aligns with the direction of the passing cAMP wave.

Nitric Oxide–cGMP Pathway Modulation in an Experimental Model of Hypoxic Pulmonary Hypertension

Manipulation of nitric oxide (NO) may enable control of progression and treatment of pulmonary hypertension (PH). Several approaches may modulate the NO-cGMP pathway in vivo. Here, we investigate the effectiveness of 3 modulatory sites: (i) the amount of l-arginine; (ii) the size of plasma NO stores that stimulate soluble guanylate cyclase; (iii) the conversion of cGMP into inactive 5′-GMP, with respect to hypoxia, to test the effectiveness of the treatments with respect to hypoxia-induced PH. Male rats (n = 80; 10/group) maintained in normoxic (21% O2) or hypoxic chambers (10% O2) for 14 days were subdivided in 4 sub-groups: placebo, l-arginine (20 mg/ml), the NO donor molsidomine (15 mg/kg in drinking water), and phoshodiesterase-5 inhibitor sildenafil (1.4 mg/kg in 0.3 ml saline, i.p.). Hypoxia depressed homeostasis and increased erythropoiesis, heart and right ventricle hypertrophy, myocardial fibrosis and apoptosis inducing pulmonary remodeling. Stimulating anyone of the 3 mechanisms that enhance the NO-cGMP pathway helped rescuing the functional and morphological changes in the cardiopulmonary system leading to improvement, sometimes normalization, of the pressures. None of the treatments affected the observed parameters in normoxia. Thus, the 3 modulatory sites are essentially similar in enhancing the NO-cGMP pathway, thereby attenuating the hypoxia-related effects that lead to pulmonary hypertension.